DESCRIPTION (Verbatim from the Applicant's Abstract): This research program is directed toward the continuing problem of biological effects of gas-body activation and cavitation in medical ultrasound. At this time, the explosive development of diagnostic ultrasound contrast agents (DUCA), which consist of suspensions of stabilized gas-bodies, presents the most pressing safety issues in medical ultrasound. The gas bodies are designed for strong activation by diagnostic ultrasound to give the enhanced image contrast, but this response also enhances mechanical perturbation in their vicinity, creating an unprecedented potential for biological effects. Cell membrane sonoporation and cell lysis in vitro, capillary rupture and extravasation in laboratory animals, and premature ventricular contractions in humans have already been shown to result from the ultrasound activation of commercial contrast agents by clinical diagnostic scanners. This research plan addresses four key questions: 1. How do DUCA induce bioeffects? Theoretical analysis and physical experiments will determine the relationships between the image enhancement process, gas body destabilization and bioeffects mechanisms. 2. What is the scope of bioeffects? In vitro studies should quickly provide data on the interaction of activated DUCA and cells, the vulnerability of phagocytic cells taking up the gas bodies, and the relative risks of different gas-body designs and image enhancement techniques. 3. What can happen in the body? Basic studies in mice and rats will examine the major physical and biological parameters controlling thresholds and magnitudes of capillary damage and extravasation. 4. Are there specific reasons for concern? Proposed research will gauge possible deleterious consequences of contrast aided diagnostic ultrasound in heart, liver, and cancerous tumors. These hypothesis driven studies should quickly elucidate the medical significance of the newly established DUCA-related bioeffects and provide the quantitative results urgently needed for guiding the safest possible integration of ultrasound contrast agents into clinical practice.